Defining circadian metabolism in NAFLD (DECIMAL)
Research type
Research Study
Full title
Defining circadian metabolism in non-alcoholic fatty liver disease (DECIMAL)
IRAS ID
291205
Contact name
Jeremy Tomlinson
Contact email
Sponsor organisation
University of Oxford/ Clinical Trials and Research Governance
Clinicaltrials.gov Identifier
15296, Project ID
Duration of Study in the UK
2 years, 8 months, 1 days
Research summary
Summary of Research
Context: Non-alcoholic fatty liver disease (NAFLD) occurs when lipid (fat) accumulates in the liver in the absence of excess alcohol and is often found alongside type 2 diabetes and obesity. It is the commonest liver disease worldwide, effecting 25% of the global population and occurs due to an imbalance between the synthesis and breakdown of lipid in the liver. Some people with NAFLD develop liver inflammation and irreversible scarring (cirrhosis) which increases the risk of developing liver failure, heart disease and liver cancer. All human beings have a 24-hour internal timer, called the ‘circadian clock’ which is co-ordinated by the brain and other organs (including the liver) and helps regulate daily rhythms in sleep, behaviour, and metabolism. Experiments in mice have shown that a large quantity of genes involved in liver fat metabolism are controlled by the circadian clock which can be influenced by loss and gain of weight. However, there have been no similar studies performed in humans.Our research study has 2 aims:
1. To define the daily variations in liver fat metabolism in overweight human participants with and without NAFLD.
2. To see if a 12-week lifestyle and weight loss programme can improve/alter the daily variations in liver fat metabolism in patients with NAFLD.Methods: 17 participants with NAFLD and 14 participants without NAFLD (confirmed using a hand held ultrasound device called FibroScanner) will have detailed investigations performed in the morning daytime (starting at 8am) and then, on a different day, have the same investigations performed in the evening (starting at 6pm). Investigations will include state-of-the art techniques with infusions of ‘stable isotopes’ to look at how much lipid is produced, exported and broken down by the liver. We will also perform biopsies of fat tissue and muscle to see how it is involved in the production and use of lipid and sugar. By comparing each participants daytime and evening results, we will be able to determine whether there is a daily variation in lipid metabolism and whether this is altered in patients with NAFLD. Following on from this, the 17 participants with NAFLD will be enrolled in a commercially available lifestyle and weight loss programme (e.g. Slimming World). After 12-weeks, an identical set of morning and evening investigations will be performed alongside a repeat liver FibroScan to look at whether the amount of fat in the liver has changed. This will determine whether weight loss can restore normal daily patterns in fat metabolism and in turn reduce liver fat.
Summary of Results
Liver fat and glucose metabolism have been shown to be under tight circadian control in cell and animal models. However, it remains unknown whether diurnal patterns exist in processes governing liver fat accumulation in humans. We performed metabolic studies during day and night in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and overweight controls. We have shown that night-time metabolic dysfunction is a hallmark of MASLD with multiple pathways up-regulated at night including liver and global insulin resistance. Insulin resistance is compounded by lower insulin levels at night due to lower insulin secretion. Diurnal differences persist when performing identical investigations after weight loss with liver fat reductions, suggesting that night-time metabolic dysfunction may be a primary driver of steatosis. These findings will help establish the optimal window for energy intake, exercise, and medication delivery in patients with MASLD.REC name
West of Scotland REC 1
REC reference
21/WS/0017
Date of REC Opinion
10 Feb 2021
REC opinion
Further Information Favourable Opinion